Abstract 3367: Tumor-derived Extracellular Vesicles as a potential PD biomarker for TEAD central pocket binder activity in liquid biopsy

Abstract

Abstract We assessed the utility of mRNAs in extracellular vesicles as biomarkers for inhibition of YAP1/TEAD signaling by the TEAD central pocket inhibitor. The field of liquid biopsies is of enormous interest for noninvasive monitoring of cancer progression and response to treatment. Extracellular Vesicles (EVs) such as exosomes, microvesicles, and apoptotic bodies, are nanoparticles found in all biological fluids. These cell-derived, small secreted vesicles convey biological information, either by surface-to-surface interaction or by shuttling bioactive molecules to a recipient cell’s cytoplasm. Because EVs harbor the cargos of their original cells, their contents may be useful as biomarkers to follow drug activity. (F. Urabi et al., 2020). We compared the effects of YAP1/TEAD inhibitor treatment on intracellular and EV-encapsulated mRNAs in three compound-sensitive tumor cell lines (and one insensitive cell line) based on TEAD inhibitor IC50 assay profiles. Cell lines were treated at four doses of YAP1/TEAD inhibitor (0.0 µM, 0.3 µM, 1.0 µM & 3.0 µM) for 24h. EVs and intracellular RNAs were isolated and profiled by RNAseq. To estimate YAP1/TEAD pathway activity, we used a transcriptomic signature identified previously by our group (L. Calvet et al., 2022) and we showed that the effects of YAP1/TEAD inhibitor treatment on the YAP1/TEAD score in intracellular mRNAs corresponded to a decrease of the score in EV-secreted RNAs. In addition, we ran an unbiased analysis to identify single transcripts in the EVs that were modulated by YAP1/TEAD inhibitor. One of the best markers identified by regression analysis was CYR61, that is part of the signature and is a well-established downstream target of YAP/TEAD pathway. In conclusion, these results suggest that the YAP1/TEAD signature in EV mRNAs represents a relevant PD biomarker to monitor YAP1/TEAD inhibitor activity and could potentially serve as a noninvasive liquid biopsy-based biomarker detection in the clinic. Citation Format: Manoel Nunes, Emmanuel Spanakis, Wilson Dos-Santos-Bele, Emilia Rabia, Stephane Soubigou, Gaelle Muzard, Odette Dos-Santos, Jack Pollard, Angela Hadjipanayis, Fabien Delahaye, Olivier Venier, Laurent Debussche, Don Jackson, Colette Dib, Iris Valtingojer, Matteo Cesaroni. Tumor-derived Extracellular Vesicles as a potential PD biomarker for TEAD central pocket binder activity in liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3367.